Field of the Invention
The disclosure is related to a radioactive tumor imaging tracer and a preparation thereof in the field of single photon emission computed tomography (SPECT), and more particularly, to a SPECT radionuclide-labeled trimeric cyclic RGD (Arg-Gly-Asp) peptide: 99mTc-4P-RGD3, comprising a 99mTc, four polyethylene glycol (PEG4) and three trimeric cyclic RGD (Arg-Gly-Asp). The medicine can be expressed by integrin αvβ3 in the tumor after intravenous injection and can function as a ligand to be combined with integrin αvβ3 receptor in tumor for tumor imaging.
Description of Related Art
According to “Cancer Facts &. Figures 2015” published on American Cancer Society, in 2007-2011, the incidence rates for selected callers in U.S. are 535.8/100,00 for male and 419.1/100,00 for female. In 2015, the estimated number of new cases for selected cancers is 1,658,370. Therefore, it is important to develop cancer detecting medicines with lower cost and simpler preparation for diagnosis and prevention of cancer.
Currently, F-18 labeled fludeoxyglucose, 18F-FDG imaging agent is used for evaluating the glucose metabolism of tumor, such that the tumor can be diagnosed, which is beneficial for the detection and treatment of tumor However, the preparation of the F-18 labeled medicine is complicated and the cost is high, meanwhile, the treatment needs to involve expensive positron emission tomography (PET) or PET/Computed Tomography (PET/CT) for imaging. Thus, the diagnostic procedure is expensive and the use in clinical application cannot be widely performed. Especially, the diagnostic procedure cannot be performed in the hospitals without PET or PET/CT scanners, and the tumor examination of PET or PET/CT cannot be widely performed.
In current researches. PET radionuclide-labeled RGD (PET RGD) can be used in clinical researches. However, the yield of the preparation of the radioactive medicine is low (˜40%), the quality control is complicated, such that the prepared medicine is even more expensive than 18F-FDG In addition, PET instruments are also needed for imaging, such that it is difficult to apply PET RGD for the clinical utilization.
As compared with 18F-FDG and PET RGD, SPECT labeled RGD cyclic peptide can be used for evaluating tumor, the preparation is simpler and can be imaged by SPECT or SPECT/CT, which are cheaper for tumor imaging, Thus, SPECT labeled RGD cyclic peptide has the advantages of lower cost and simple technique for future development. Especially, 99mTc labeled cyclic peptide imaging can be used for evaluating the level of integrin αvβ3 in tumor, which is different from the 18F-FDG method. 99mTc labeled cyclic peptide imaging can provide another important diagnostic value for malignant degree of tumor in diversity of tumor biological behavior.
Integrin αvβ3 is the integrin which has been studied the most. Integrin αvβ3 is expressed on the surface of multiple tumor cells and tumor neovasculars, such as glioma, lung tumor, thyroid tumor, hepatic tumor, teratoma and breast tumor. Integrin αvβ3 is not expressed or almost unexpressed in mature endothelial cells and most of the normal cells. The formation of neovasculars and lymphatics play an important role in tumor occurrence, development and migration. The formation of tumor neovasculars would enhance the tumor growing and migrating, and the formation of lymphatics is directly related to tumor migration. αvβ3 acceptors mediate the adhesion and migration of tumor cells and play an important role in the formation of tumor neovasculars and lymphatics migration. The expression level of αvβ3 is related to malignant phenotypes of malignant tumor, such as invasion and metastasis, and can be servers as an indicator of evaluating the malignant tumor in prognosis.
Integrin is a group of transmembrane glycoprotein, which is a heterodimer having a α sub unit and a β sub unit combined by non-covalent bonds. It is also an acceptor of extracellular matrix proteins. It is specifically combined with receptor recognition sequence RGD of the extracellular matrix proteins (such as fibronectin, glass-binding protein, laminin, collagen and so forth). Integrin controls the formation of neovasculars and lymphatics. According to multiple researches, integrin controls proteolytic enzymes, such as matrix metalloproteinase, and integrin directly involves in degradation of extracellular matrix and enhances migration of tumor. The rich expression of integrin is the important molecule in enhancing migration and invasion of tumor cells and vascular endothelial cells. Integrin can directly mediate adhesive bonding of tumor cells and matrix proteins and involves in controlling cytoskeleton and cell proliferation in cells.
According to present researches (as shown in Annotations 1-3), the binding affinity of RGD cyclic peptide multimer with the target is increased with the increase of the amount of RGD cyclic peptide in even number for imaging tumor (RGD8>RGD4>RGD2). However, when the amount of RGD cyclic peptide is too large, it causes problem in imaging. The problem mainly includes having a lower target-background-ratio (TBR) due to the intake of non-target tissues (background), such that the quality of imaging is deteriorated. Thus, the RGD medicine with low affinity and high background intake cannot be practically used for clinical applications. Therefore, it is important to develop a RGD medicine having higher tumor intake and lower background intake.                1. 64Cu-labeled tetrameric and octameric RGD peptides for small-animal PET of tumor αvβ3 integrin expression. Li Z B, Cai W, Cao Q, Chen K, Wu Z. He L, Chen X. J Nucl Med. 2007 July; 48(7):1162-71.        2. 68Ga-labeled multimeric RGD peptides for microPET imaging of integrin αvβ3 expression. Li Z B, Chen K, Chen X. Eur J Nucl Med Mol Imaging. 2008 June; 35(6):1100-8.        3. Micro-PET imaging of αvβ3-integrin expression with 18F-labeled dimeric RGD peptide. Chen X, Tohrne M, Park R, Hou Y, Bading J R, Conti P S. Mol Imaging. 2004 April; 3(2):96-104.        
According to the present researches, 99mTc-labeled RGD cyclic peptide (99mTc-3P-RGD2) and 99mTc-labeled RGD galactose dimer (99mTc-Galacto-RGD2) imaging agent are proved to have great affinity with the expression of integrin αvβ3 in malignant tumor (as shown in Annotations 4-5), and they can be imaged by SPECT or SPECT/CT, which can be served as economical agents for tumor diagnosis. However, these two agents are found to still have a relatively high radioactive level of background in abdomen organs in animal bodies, such that the performance of imaging is affected, and the applicability value in abdomen tumor diagnosis is limited.                4. Integrin αvβ3-targeted radiotracer (99m)Tc-3P-RGD2, useful for noninvasive monitoring of breast tumor response to antiangiogenic linifanib therapy but not anti-integrin α(v)β3 RGD2 therapy. Ji S, Zheng Y, Shao G, Zhou Y, Liu S. Theranostics. 2013; 3(11):816-30.        5. (99m)Tc-Galacto-RGD2: a novel 99mTc-labeled cyclic RGD peptide dimer useful for tumor imaging. Ji S, Czerwinski A, Zhou Y. Shao G, Valenzuela F, Sowinski P. Chauhan S, Pennington M, Liu S. Mol Pharm. 2013; 10(9):3304-14.        